Sitosterolemia

Summary

Sitosterolemia (MONDO:0008863) is a disease caused by ABCG8 (GenCC Definitive), with 3 cohort genes and 4 clinical trials. Top therapeutic interventions include colesevelam, ezetimibe, and fish oil.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABCG8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 421
• Phenotypes (HPO): 13
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000991	Xanthomatosis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001878	Hemolytic anemia	Frequent (30-79%)
HP:0001902	Giant platelets	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0004446	Stomatocytosis	Frequent (30-79%)
HP:0005181	Premature coronary artery atherosclerosis	Frequent (30-79%)
HP:0033341	Elevated circulating sitosterol concentration	Frequent (30-79%)
HP:0040185	Macrothrombocytopenia	Frequent (30-79%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0005059	Arthralgia/arthritis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	sitosterolemia
Mondo ID	MONDO:0008863
MeSH	C537345
OMIM	210250, 215250
Orphanet	2882, 101022
DOID	DOID:0090019
NCIT	C125694
SNOMED CT	238104009
UMLS	C0342907
MedGen	87466
GARD	0007653
MedDRA	10063985
NORD	1911
Is cancer (heuristic)	no

Also known as: phytosterolemia · plant sterol storage disease · retention of dietary cholesterol and abnormal retention of non-cholesterol sterols in the body · sitosterolemia · STSL

Data availability: 421 ClinVar variants · 3 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › sitosterolemia

Related subtypes (28): familial apolipoprotein C-II deficiency, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata type 1, apparent mineralocorticoid excess, GM1 gangliosidosis type 1, familial lipoprotein lipase deficiency, sea-blue histiocyte syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, Barth syndrome, CHILD syndrome, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, Krabbe disease due to saposin A deficiency, lipoprotein glomerulopathy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, hyperlipoproteinemia, type 1D, intellectual disability, autosomal recessive 53, hyperphosphatasia-intellectual disability syndrome, mevalonate kinase deficiency, fatty acid hydroxylase-associated neurodegeneration, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction, peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain, lysosomal acid lipase deficiency

Subtypes (2): sitosterolemia 1, sitosterolemia 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

421 retrieved; paginated sample, class counts are floors:

152 likely benign, 136 uncertain significance, 64 conflicting classifications of pathogenicity, 26 pathogenic, 15 likely pathogenic, 12 benign/likely benign, 12 pathogenic/likely pathogenic, 3 benign, 1 benign/likely benign; association

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120119	NM_022436.3(ABCG5):c.751C>T (p.Gln251Ter)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
1437547	NM_022436.3(ABCG5):c.1138del (p.Leu379_Val380insTer)	ABCG5	Pathogenic	criteria provided, single submitter
1514001	NC_000002.11:g.(?44040255)(44041748_?)del	ABCG5	Pathogenic	criteria provided, single submitter
1704642	NM_022436.3(ABCG5):c.64C>T (p.Gln22Ter)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
1771014	NM_022436.3(ABCG5):c.136del (p.Ser46fs)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
1907244	NM_022436.3(ABCG5):c.1657C>T (p.Gln553Ter)	ABCG5	Pathogenic	criteria provided, single submitter
2023964	NM_022436.3(ABCG5):c.1573C>T (p.Gln525Ter)	ABCG5	Pathogenic	criteria provided, single submitter
2111434	NM_022436.3(ABCG5):c.1681dup (p.Ile561fs)	ABCG5	Pathogenic	criteria provided, single submitter
2203052	NM_022436.3(ABCG5):c.1528del (p.His510fs)	ABCG5	Pathogenic	criteria provided, single submitter
2203054	NM_022436.3(ABCG5):c.1311C>G (p.Asn437Lys)	ABCG5	Pathogenic	criteria provided, single submitter
222478	NM_022436.3(ABCG5):c.978del (p.Glu326fs)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426862	NM_022436.3(ABCG5):c.547C>T (p.Arg183Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2722141	NM_022436.3(ABCG5):c.1763-1G>A	ABCG5	Pathogenic	criteria provided, single submitter
2740333	NM_022436.3(ABCG5):c.367G>T (p.Glu123Ter)	ABCG5	Pathogenic	criteria provided, single submitter
2889432	NM_022436.3(ABCG5):c.1273C>T (p.Gln425Ter)	ABCG5	Pathogenic	criteria provided, single submitter
2903014	NM_022436.3(ABCG5):c.1528dup (p.His510fs)	ABCG5	Pathogenic	criteria provided, single submitter
30485	NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247168	NC_000002.11:g.(?44065656)(44105052_?)del	ABCG5	Pathogenic	criteria provided, single submitter
3627815	NM_022436.3(ABCG5):c.1735G>T (p.Glu579Ter)	ABCG5	Pathogenic	criteria provided, single submitter
3671907	NM_022436.3(ABCG5):c.145del (p.His49fs)	ABCG5	Pathogenic	criteria provided, single submitter
3715753	NM_022436.3(ABCG5):c.187C>T (p.Gln63Ter)	ABCG5	Pathogenic	criteria provided, single submitter
3720320	NM_022436.3(ABCG5):c.436G>T (p.Glu146Ter)	ABCG5	Pathogenic	criteria provided, single submitter
3720321	NM_022436.3(ABCG5):c.144-1G>A	ABCG5	Pathogenic	criteria provided, single submitter
3992479	NM_022436.3(ABCG5):c.321del (p.Thr108fs)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
4713262	NM_022436.3(ABCG5):c.1435del (p.Thr479fs)	ABCG5	Pathogenic	criteria provided, single submitter
4808924	NM_022436.3(ABCG5):c.904+1G>C	ABCG5	Pathogenic	criteria provided, single submitter
4976	NM_022436.3(ABCG5):c.1222C>T (p.Arg408Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4977	NM_022436.3(ABCG5):c.727C>T (p.Arg243Ter)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
4978	NM_022436.3(ABCG5):c.1256G>A (p.Arg419His)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
4980	NM_022436.3(ABCG5):c.1166G>A (p.Arg389His)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABCG5	Definitive	Autosomal recessive	sitosterolemia 1	5
ABCG8	Definitive	Autosomal recessive	sitosterolemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia
ABCG8	Orphanet:2882	Sitosterolemia
ABCG8	Orphanet:391665	Homozygous familial hypercholesterolemia
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	gencc,clinvar
ABCG8	HGNC:13887	ENSG00000143921	Q9H221	ATP-binding cassette sub-family G member 8	gencc,clinvar
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
ABCG8	ATP-binding cassette sub-family G member 8	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
DYNC2LI1	Cytoplasmic dynein 2 light intermediate chain 1	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	2	51.9×	1e-03
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
ABCG8	Transporter	yes		ABC_transporter-like_ATP-bd, ABC2_TM, ABC_transporter-like_CS
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	2
right lobe of liver	2
duodenum	1
liver	1
bronchial epithelial cell	1
mucosa of paranasal sinus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum
ABCG8	66	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
ABCG8	1,920
DYNC2LI1	852

Intra-cohort edges

A	B	Sources
ABCG5	ABCG8	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
ABCG8	Q9H221	8
DYNC2LI1	Q8TCX1	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCG8 causes GBD4 and sitosterolemia	2	3806.7×	3e-07	ABCG5, ABCG8
Defective ABCG5 causes sitosterolemia	2	3806.7×	3e-07	ABCG5, ABCG8
ABC transporters in lipid homeostasis	2	400.7×	3e-05	ABCG5, ABCG8
ABC transporter disorders	2	292.8×	5e-05	ABCG5, ABCG8
NR1H2 and NR1H3-mediated signaling	2	262.5×	5e-05	ABCG5, ABCG8
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	2	205.8×	7e-05	ABCG5, ABCG8
Disorders of transmembrane transporters	2	92.8×	3e-04	ABCG5, ABCG8
ABC-family protein mediated transport	2	81.0×	3e-04	ABCG5, ABCG8
Signaling by Nuclear Receptors	2	68.0×	4e-04	ABCG5, ABCG8
Transport of small molecules	2	16.8×	0.006	ABCG5, ABCG8
Intraflagellar transport	1	66.8×	0.018	DYNC2LI1
Disease	2	8.7×	0.018	ABCG5, ABCG8
Signal Transduction	2	6.8×	0.027	ABCG5, ABCG8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of intestinal phytosterol absorption	2	5617.3×	2e-07	ABCG5, ABCG8
negative regulation of intestinal cholesterol absorption	2	5617.3×	2e-07	ABCG5, ABCG8
sterol transport	2	1872.4×	2e-06	ABCG5, ABCG8
intestinal cholesterol absorption	2	936.2×	6e-06	ABCG5, ABCG8
response to muscle activity	2	387.4×	3e-05	ABCG5, ABCG8
cholesterol efflux	2	351.1×	3e-05	ABCG5, ABCG8
triglyceride homeostasis	2	321.0×	3e-05	ABCG5, ABCG8
response to nutrient	2	197.1×	7e-05	ABCG5, ABCG8
transmembrane transport	2	112.3×	2e-04	ABCG5, ABCG8
cholesterol homeostasis	2	104.0×	2e-04	ABCG5, ABCG8
response to xenobiotic stimulus	2	46.0×	1e-03	ABCG5, ABCG8
intraciliary transport involved in cilium assembly	1	802.5×	0.002	DYNC2LI1
intraciliary retrograde transport	1	374.5×	0.003	DYNC2LI1
phospholipid transport	1	234.1×	0.005	ABCG8
regulation of cilium assembly	1	200.6×	0.006	DYNC2LI1
response to ionizing radiation	1	137.0×	0.008	ABCG5
determination of left/right symmetry	1	85.1×	0.012	DYNC2LI1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCG5	0	0
ABCG8	0	0
DYNC2LI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ABCG5, ABCG8
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DYNC2LI1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCG5	0	—
ABCG8	0	—
DYNC2LI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00004481	Not specified	COMPLETED	Genetic Study of Sitosterolemia
NCT00531128	Not specified	COMPLETED	The Effect of Dietary Sitosterol on Blood Sugar and Cholesterol
NCT01584206	Not specified	COMPLETED	Sitosterolemia Metabolism
NCT01948648	Not specified	UNKNOWN	Effects of Fish Oil and Colesevelam (STAIR7007)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
COLESEVELAM	4	1
EZETIMIBE	4	1
FISH OIL	4	1
CHEMBL1201677	0	1